EP1202983B1 - Verfahren zur herstellung von lösemittelfreier alpha-liponsäure - Google Patents

Verfahren zur herstellung von lösemittelfreier alpha-liponsäure Download PDF

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Publication number
EP1202983B1
EP1202983B1 EP00954620A EP00954620A EP1202983B1 EP 1202983 B1 EP1202983 B1 EP 1202983B1 EP 00954620 A EP00954620 A EP 00954620A EP 00954620 A EP00954620 A EP 00954620A EP 1202983 B1 EP1202983 B1 EP 1202983B1
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EP
European Patent Office
Prior art keywords
acid
lipoic acid
lipoic
previous
adjusted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP00954620A
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German (de)
English (en)
French (fr)
Other versions
EP1202983A1 (de
Inventor
Hans Schuhbauer
Stefan Winkler
Ansgar Gruber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Alzchem Trostberg GmbH
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Degussa GmbH
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid

Definitions

  • the present invention relates to a process for the preparation of solvent-free ⁇ -lipoic acid.
  • ⁇ -lipoic acid (thioctic acid, 1,2-dithiolane-3-pentanoic acid) is a natural product occurring in the form of the R-enantiomer in low concentrations in plant and animal cells.
  • the ⁇ -lipoic acid originally discovered as a growth factor acts physiologically in hydrophilic and lipophilic media as a coenzyme of the oxidative decarboxylation of ⁇ -ketocarboxylic acids (e.g., pyruvates) and as an antioxidant, and is capable of regenerating vitamin C, vitamin E, glutathione, and coenzyme Q10.
  • Racemic ⁇ -lipoic acid is approved for the treatment of liver diseases and neuropathies (e.g., diabetic polyneuropathy); their use as an effective inhibitor of replication of HIV-1 viruses has been discussed (see Klin. Weinschr., 1991, 69 (15), 722-724).
  • the racemate of ⁇ -lipoic acid also has cytoprotective, anti-inflammatory and antinociceptive (analgesic) properties, and it has been found that in the pure optical isomers of ⁇ -lipoic acid (R- ⁇ -lipoic acid or S- ⁇ -lipoic acid) in contrast to the racemate the R-enantiomer shows a predominantly antiphlogistic and the S-enantiomer a predominantly antinociceptive profile of action (compare EP 0 812 590 A2).
  • the usual purification method for crude ⁇ -lipoic acid is a recrystallization from solvents (eg from n-pentane, cyclohexane, methylcyclohexane, ethyl acetate) or mixtures of solvents (eg from ethyl acetate and hexane), as described, for example, in Brookes et al., J. Chem Soc. Perkin Trans. 1 1988, 9, Segre et al., J. Am. Chem. Soc. 1957, 3503, Walton et al., J. Am. Chem. Soc. 1955, 77, 5144, Acker et al., J. Am. Chem. Soc.
  • the present invention is therefore based on the object to provide a process for the preparation of solvent-free ⁇ -lipoic acid, which does not have the disadvantages of the known methods, but in a simple manner allows the production of ⁇ -lipoic acid containing no organic residual solvent more.
  • the ⁇ -lipoic acid to be purified in step a) is advantageously dissolved in an aqueous alkaline solution having a pH of 7.5 to 16.0, preferably of 9.0 to 14.0.
  • the alkaline solution may contain the usual bases in the form of hydroxides, carbonates and bicarbonates of alkali or alkaline earth metals (such as sodium, potassium, calcium and magnesium), ammonia or primary, secondary or tertiary amines (such as benzylamine, diisopropylamine, triethylamine) ,
  • the crude ⁇ -lipoic acid used in step a) can in this case be prepared by means of any desired process.
  • the ⁇ -lipoic acid for example be prepared by recrystallization with an organic solvent or be crude ⁇ -lipoic acid in the absence of organic solvents.
  • racemic ⁇ -lipoic acid and an enantiomerically pure R- (+) - ⁇ -lipoic acid or S - (-) - ⁇ -lipoic acid or any mixtures thereof can be used in the process according to the invention.
  • a salt of the ⁇ -lipoic acid can also be dissolved in water and then made alkaline, e.g. with the bases already described, expedient to a pH of 7.5 to 16.0, preferably 9.0 to 14.0.
  • alkali such as sodium or potassium
  • alkaline earth metal salts such as calcium or magnesium
  • other salts of ⁇ -lipoic acid can be used, their cations may consist in particular of the elements zinc, iron, copper, palladium, vanadium and selenium.
  • ⁇ -lipoic acid salts of organic cations such as open-chain or cyclic ammonium compounds (such as ammonium, methylammonium, benzylmethylammonium or tetramethylammonium cations), complex cations (with metallic central atoms such as iron (III), chromium (III) or cobalt (II) and neutral, cationic or anionic ligands (such as water (H 2 O), ammonia (NH 3 ), carbonyl (CO), cyano (CN) or nitroso (NO)) or oxo cations (such as oxovanadium ( V) (VO 2 + ) or oxovanadium (IV) (VO 2+ )) can be used as starting compounds.
  • organic cations such as open-chain or cyclic ammonium compounds (such as ammonium, methylammonium, benzylmethylammonium or tetramethylammonium cations), complex cations (
  • the content of ⁇ -lipoic acid in step a) can be varied within wide limits. However, it has proved to be advantageous to adjust the concentration of ⁇ -lipoic acid in the aqueous alkaline solution to 0.01 to 15 wt .-%, preferably to 0.1 to 5 wt .-%.
  • activated carbon is added to the aqueous alkaline solution in stage a) before the implementation of stage b) in an amount of from 0.01 to 50% by weight, based on the ⁇ -lipoic acid equivalents in the solution.
  • activated carbons it is additionally possible to separate off interfering impurities, by-products and / or residual solvents.
  • Norit SX Plus, Norit Pureflow 1, Norit Pureflow C or Norit SA Plus activated carbons have proved particularly advantageous.
  • step b) possibly present solid impurities from the aqueous solution of step a) are separated. Suitable are the usual methods such as filtration, centrifugation and the like.
  • the aqueous solution from stage a) or b) is adjusted in the following stage c) with the aid of an acid to a pH of from 1.0 to 5.0, preferably from 1.0 to 4.0.
  • an acid to a pH of from 1.0 to 5.0, preferably from 1.0 to 4.0.
  • inorganic and organic acids can be used. From the group of inorganic acids, the usual mineral acids, e.g. Hydrohalic acid (in the form of hydrochloric or hydrobromic acid), nitric acid, sulfuric acid and phosphoric acid particularly well proven.
  • the pH adjustment can also be made with organic acids, e.g.
  • an aliphatic carboxylic acid having 1 to 6 carbon atoms e.g., formic acid, acetic acid
  • an aromatic carboxylic acid e.g., benzoic acid
  • a halogenated or oxygenated carboxylic acid e.g., chloroacetic acid, trifluoroacetic acid, pyruvic acid
  • an aliphatic or aromatic sulfonic acid e.g., methanesulfonic acid, toluenesulfonic acid.
  • steps a) to c) is not critical, but it is suitably chosen in the range of -50 to +60 ° C, with room temperatures are preferred.
  • step d) the lipoic acid precipitated by the pH adjustment is separated, preferably by filtration or centrifugation.
  • the temperature in step d) is suitably selected in the range of -50 to +60 ° C, preferably in the range of -10 to +10 ° C.
  • the purified ⁇ -lipoic acid obtained from stage d) contains, as the only secondary constituent, the physiologically completely harmless solvent water.
  • the storage stability of moist, semi-moist or dry ⁇ -lipoic acid is not affected by the water content. If desired, it is possible to reduce the water content of the purified and dried ⁇ -lipoic acid to values of ⁇ 0.5, in particular ⁇ 0.1% by weight, by conventional drying, for example in a fluidized bed dryer, rotary dryer, conical screw mixer or double-cone mixer ,
  • the process according to the invention thus represents a substantial improvement in the field of purification of racemic or enantiomerically pure ⁇ -lipoic acid, because the quality requirements for active pharmaceutical ingredients and medical products are fully taken into account by a complete removal of all residual solvent traces.
  • the resulting ⁇ -lipoic acid (about 1 g) is dissolved in 10 ml of p-chlorotoluene and an aliquot of this solution is injected directly into a gas chromatograph.
  • the detection is done by FID (flame ionization detection) against an external standard. Detection and quantification limits are summarized in Table 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP00954620A 1999-08-14 2000-08-10 Verfahren zur herstellung von lösemittelfreier alpha-liponsäure Expired - Lifetime EP1202983B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19938621A DE19938621A1 (de) 1999-08-14 1999-08-14 Verfahren zur Herstellung von lösemittelfreier alpha-Liponsäure
DE19938621 1999-08-14
PCT/EP2000/007802 WO2001012620A1 (de) 1999-08-14 2000-08-10 VERFAHREN ZUR HERSTELLUNG VON LÖSEMITTELFREIER α-LIPONSÄURE

Publications (2)

Publication Number Publication Date
EP1202983A1 EP1202983A1 (de) 2002-05-08
EP1202983B1 true EP1202983B1 (de) 2003-01-29

Family

ID=7918432

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00954620A Expired - Lifetime EP1202983B1 (de) 1999-08-14 2000-08-10 Verfahren zur herstellung von lösemittelfreier alpha-liponsäure

Country Status (11)

Country Link
US (1) US6462202B1 (zh)
EP (1) EP1202983B1 (zh)
CN (1) CN1131227C (zh)
AT (1) ATE231854T1 (zh)
AU (1) AU6701300A (zh)
CA (1) CA2380495C (zh)
DE (2) DE19938621A1 (zh)
DK (1) DK1202983T3 (zh)
ES (1) ES2187483T3 (zh)
PT (1) PT1202983E (zh)
WO (1) WO2001012620A1 (zh)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1319196B1 (it) * 2000-10-10 2003-09-26 Laboratorio Chimico Int Spa Sintesi dell'acido r(+)alfa-lipoico.
IT1319195B1 (it) * 2000-10-10 2003-09-26 Laboratorio Chimico Int Spa Processo per la produzione dell'acido r(+)alfa-lipoico.
DE10159245A1 (de) * 2001-12-03 2003-06-18 Degussa Stabile, saure, wässrige Lösung enthaltend alpha-Liponsäure(-Derivate), Verfahren zu deren Herstellung sowie ihre Verwendung
DE10201464B4 (de) * 2002-01-16 2005-06-16 Viatris Gmbh & Co. Kg Verfahren zur Herstellung reiner Thioctsäure
ITMI20050466A1 (it) * 2005-03-22 2006-09-23 Laboratorio Chimico Int Spa Processo di purificazione in acqua di acido tiottico
CN100375745C (zh) * 2005-12-21 2008-03-19 重庆药友制药有限责任公司 硫辛酸的精制方法
CN100387593C (zh) * 2006-01-26 2008-05-14 南京师范大学 连续逆流液液萃取分离二硫辛酸与乙醇及碱水溶液的方法
DE102007038849A1 (de) 2007-08-16 2009-02-19 Adscil Gmbh Verwendung von R(+)-alpha-Liponsäure zur Behandlung der kryptogenen Neuropathie
RU2011124739A (ru) * 2008-12-01 2013-01-10 Инваск Терапьютикс, Инк. Композиции, содержащие ингибиторы системы ренин-ангиотензин альдостерона и соединения липоевой кислоты, и их применение для лечения заболеваний, связанных с системой ренин-ангиотензин альдостерона
CN102603709B (zh) * 2012-03-02 2013-09-25 海南灵康制药有限公司 一种硫辛酸化合物及其制法
CN105798322B (zh) * 2016-03-17 2018-04-24 湖北大学 银纳米簇的制备方法及其应用
CN114163418A (zh) * 2021-12-24 2022-03-11 山东龙辰药业有限公司 一种右旋硫辛酸的合成方法
CN115490861B (zh) * 2022-08-22 2023-11-17 北京化工大学 一种聚硫辛酸可再生高分子材料制备方法

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19726519A1 (de) 1997-06-23 1998-12-24 Asta Medica Ag Verfahren zur Herstellung trockener Thioctsäure

Also Published As

Publication number Publication date
CN1131227C (zh) 2003-12-17
DK1202983T3 (da) 2003-05-26
CA2380495C (en) 2006-10-17
WO2001012620A1 (de) 2001-02-22
DE19938621A1 (de) 2001-02-22
ES2187483T3 (es) 2003-06-16
PT1202983E (pt) 2003-06-30
ATE231854T1 (de) 2003-02-15
AU6701300A (en) 2001-03-13
EP1202983A1 (de) 2002-05-08
DE50001184D1 (de) 2003-03-06
CN1354748A (zh) 2002-06-19
US6462202B1 (en) 2002-10-08
CA2380495A1 (en) 2001-02-22

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